Herpesvirus infections in humans can be induced by six known human herpesviruses, the most common being herpes simplex virus and varicella-zoster virus. There are also many animal herpesviruses.
Herpes simplex viruses can be divided into two serotypes, type 1 (HSV-1) and type 2 (HSV-2), the clinical manifestations of which range from benign self-limiting oral-facial and genital infections to potentially life threatening conditions like encephalitis and generalized neonatal infections.
Oral-facial HSV infections are primarily caused by HSV-1. Following a primary infection in childhood the virus becomes latent in the sensory nerve cells, most often the trigeminal ganglion, for the rest of the invididual's life. The virus can subsequently be reactivated at different times. Following a reactivation in the nerve cell, the virus is transported through the nerves to the skin and subsequently develops a recurrent oral-facial HSV infection more commonly known as a cold sore. About half of the patients experience prodromal symptoms such as pain, burning or itching at the site of the subsequent eruption. The condition is generally rapidly self-limiting and a typical episode will heal in around 10 days from the first symptoms. Viral replication in the lip is initiated early and maximal virus load is obtained 24 hours following onset of the recurrence. The virus concentration is then dramatically reduced and virus can not be isolated 70-80 hours after onset in the typical patient.
The clinical presentation of genital HSV infections is similar to the oral-facial infections with a couple of important exceptions. Genital HSV infections are most often caused by HSV-2 and following a primary infection the virus will latently infect sensory or autonomic ganglions. Reactivation will produce the local recurrent lesions that are characteristic of the herpes infection on or near the genitals.
Varicella-zoster virus (VZV) is also a member of the herpesvirus group. The primary infection is known to cause chickenpox. Like HSV, VZV becomes latent following the primary infection and can like HSV be reactivated as herpes zoster later on in life. Zoster usually results in skin rash and intensive acute pain. In 30% of the patients, the pain can be prolonged and continue for weeks or months after the rash has cleared up.
Cytomegalovirus (CMV), Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6 ) are the other known human herpesviruses.
Primary CMV infection in the normal host is usually not accompanied by symptoms, but occasionally symptoms of CMV mononucleosis may appear. In the blood, CMV resides mainly in the polymorphonuclear leucocytes, but monocytes and occasionally T lymphocytes may harbor CMV in a form as yet unidentified.
Most human EBV infections start in the oropharyngeal epithelium. Early in the course of primary infection EBV infects B lymphocytes. EBV does not usually replicate productively in B lymphocytes but instead establishes latent infection.
HIV is a retrovirus which infects and destroys lymphocytes bearing the CD4 cell marker, causing progressive immunodeficiency. Foscarnet inhibits the reverse transcriptase of HIV and shows antiviral activity against the replication of HIV in vitro.
There are a number of antiviral agents which are active against the human herpesviruses. However, so far there has only been limited clinical success in the treatment of recurrent herpesvirus infections in immunocompetent patients.
Foscarnet, the hexahydrate of the trisodium salt of phosphonoformic acid (sodium phosphonoformate hexahydrate), is a well-known antiviral agent with a broad antiviral spectrum, acting by direct inhibition of viral DNA polymerase in herpesviruses and hepatitis B virus and of viral reverse transcriptase in retroviruses. Foscarnet has been approved for clinical use for systemic, that is intravenous, treatment of CMV retinitis and acyclovir-resistent HSV infections in AIDS patients. A side-effect of said treatment is a renal function impairment as well as other symptoms which can be tolerated in the treatment of a life-threatening condition but hardly in the treatment of benign, self-limiting recurrent HSV infections in immunocompetent patients.
Acyclovir (ACV), 9-[(2-hydroxyethoxy)methyl]guanine, is a major antiviral drug which has been used in the treatment of a variety of herpesvirus infections. It can be administered as topical, oral, or intravenous preparations, the topical preparations being less effective. Acyclovir therapy is associated with very few adverse effects. Valaciclovir or L-valyl acyclovir is a prodrug of acyclovir. The antiherpesvirus agent penciclovir, 9-(4-hydroxy-3 -hydroxymethylbut-1-yl)- guanine, has a spectrum of activity against human herpesviruses similar to that of acyclovir. Famciclovir, the 6-deoxy derivative of penciclovir, is converted to penciclovir in the body by means of oxidative metabolism.
Nucleoside analogues such as the guanosine analogues acyclovir, valaciclovir, penciclovir and famciclovir have a more narrow antiviral spectrum than foscarnet and mainly show effect against HSV-1 and HSV-2 and VZV viruses. These compounds do not act directly on the viral DNA polymerase like foscarnet, but have to be phosphorylated three times by viral and cellular enzymes for inhibition of the viral polymerase to be achieved. They are primarily administered as oral compositions although other ways of administration, such as parenteral, are also possible.
Some problems in treating herpesvirus infections by parenteral administration are the high doses and large volumes to be administered and the short half-life of the antiviral compound in the circulation.
When the herpes infection is limited to the skin or mucous membranes, topical therapy could be advantageous. This will reduce the exposure of the body to the active substance and allow higher drug concentrations to be used which could make it possible to reach higher local concentrations in the part of the skin where the virus replicates.
Although foscarnet has a proven activity against all human herpesvirus in vitro, testing of foscarnet, applied topically, against recurrent herpes simplex virus infections in immunocompetent patients has only met with a moderate degree of success. The healing time of lesions upon such treatment is shortened by approximately one day. In said tests foscarnet was applied in a conventional cream formulation. A topical administration of foscarnet in a 3% formulation is known to cause irritation of mucous membranes or the skin, in the genital region making the medical treatment painful. One purpose of this invention is, therefore, to find a composition of foscarnet that elicits a very low degree of tissue irritation in addition to a potent antiviral effect.
The clinical effectiveness of the nucleoside analogues acyclovir, valaciclovir, penciclovir and famciclovir on recurrent cutaneous virus diseases is, as with foscarnet, limited. With topical treatment the healing time is only reduced by approximately one day. Another purpose of the invention is, therefore, to find a composition of an antiviral compound selected from the group consisting of foscarnet, acyclovir, valaciclovir, penciclovir and famciclovir which will give a substantially reduced healing time.